Increased Tolerance to Endotoxin by Granulocyte-Macrophage Colony-Stimulating Factor-Deficient Mice

The contribution of granulocyte-macrophage CSF (GM-CSF) to endotoxin-mediated septic shock has been assessed by treating GM-CSF-deficient mice with LPS. Hypothermia and loss in body weight were markedly attenuated in LPS-treated GM-CSF-deficient mice compared with similarly treated control mice; moreover, the levels of circulating IFN-γ, IL-1α, and IL-6 were lower in LPS-treated GM-CSF-deficient mice than LPS-treated control mice. Intriguingly, the peak levels of TNF-α in response to LPS treatment were the same in the serum of GM-CSF-deficient mice and control mice, although in GM-CSF-deficient mice, TNF-α persisted longer. Activation of macrophages by LPS, resulting in expression of cytokines including TNF-α and IL-1, is thought to underlie endotoxin-mediated effects. Accordingly, the response of peritoneal macrophages from GM-CSF-deficient mice to LPS was studied in vitro. LPS-stimulated peritoneal macrophages from GM-CSF-deficient mice produced significantly less IL-1α and nitric oxide than macrophages from wild-type mice, although there was no difference in TNF-α production. Collectively, these observations indicate that GM-CSF contributes to cytokine production in LPS-mediated septic shock, and that the attenuated production of these secondary cytokines (IFN-γ, IL-1α, and IL-6) may contribute to the endotoxin-resistant phenotype of GM-CSF-deficient mice.